Leukemias are often associated with chromosomal translocations that give rise to fusion proteins which may deregulate cellular signaling or transcription. Our group cloned and characterized two variant fusion proteins involved in acute promyelocytic leukemia (APL), NPM-RAR-alpha and NuMA-RAR-alpha, which are both aberrant transcription factors; we are especially interested in understanding the roles of these fusion proteins in the cell. Specifically, we use cell lines, mouse models and human patient samples in order to understand leukemia biology. The questions we are most interested in include:

1. What are the cell biology effects of the APL fusion proteins? While most studies have focused on the APL fusions as transcription factors, more recent evidence has suggested that these proteins behave distinctly and have effects through protein-protein interactions on other signaling pathways within the leukemic cell. We are applying the same concept as above, and hypothesizing that there may be a common set of interactions and/or deregulated pathways shared by all APL fusion proteins, and are characterizing the protein-protein interactions of the fusions in order to find this out.
2. What are the necessary secondary events in leukemia development? Previous studies have indicated that the APL fusions are necessary, but insufficient, for the development of leukemia in mice. This suggests that additional genetic ''events'' may cooperate with the fusions in leukemia. We are addressing this question through the above studies, and also through genetic studies of the hCG-NuMA-RAR-alpha mouse model that we previously developed and characterized.

What are the common downstream genetic targets of the APL fusion proteins? APL is associated with seven known fusion proteins, all of which involve the RAR-alpha transcription factor. Yet, all fusion proteins give rise to the same disease. We hypothesize that this is because all fusion proteins have a common set of direct transcriptional targets, and are utilizing gene expression arrays and ChIP-on-chip technology to address this issue.